WO2013017661A1 - Méthode d'évaluation de la réponse pharmacogénétique au traitement par des sels de lithium du trouble bipolaire - Google Patents

Méthode d'évaluation de la réponse pharmacogénétique au traitement par des sels de lithium du trouble bipolaire Download PDF

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WO2013017661A1
WO2013017661A1 PCT/EP2012/065157 EP2012065157W WO2013017661A1 WO 2013017661 A1 WO2013017661 A1 WO 2013017661A1 EP 2012065157 W EP2012065157 W EP 2012065157W WO 2013017661 A1 WO2013017661 A1 WO 2013017661A1
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response
treatment
lithium
gene
patients
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Maria DEL ZOMPO
Alessio SQUASSINA
George P. PATRINOS
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Universita' Degli Studi Di Cagliari
Fase 1 S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention relates to a method for pharmacogenetic assessment of the response to treatment with lithium salts in patients with bipolar disorder based on the detection of a polymorphism located in intron 1 of the amiloride-sensitive cation channel 1 , neuronal gene (ACCN1 ).
  • bipolar disorder falls in the class of mood disorders and indicates a clinical picture characterized by recurrent major affective episodes of opposite polarity, i.e. alternating between a maniacal state and a depressive state, associated with altered thought processes and behaviours. Mood disorder episodes are interspersed with more or less brief periods of relative wellness.
  • the estimated prevalence of bipolar disorder during lifetime is 4-5% in the general population, with mean age of onset at 18 years for males and 20 years for females [1 ].
  • the natural course of BD often leads to gradual deterioration of functional performance of affected individuals with impairment of one or more functional areas: loss of employment, disruption of interpersonal relationships, substance abuse, legal problems, hospitalizations.
  • suicide is the leading cause of death in people with BD with a 3-6 fold higher mortality rate than the general population.
  • BD is a complex and heterogeneous disorder in which biological and environmental factors interact to modulate disorder susceptibility. This complexity accounts at least in part for the lack of clear identification of molecular determinants involved in BD susceptibility, but epidemiological data show high heritability of this condition [2].
  • lithium salts are the drug of choice for treatment of bipolar disorder.
  • lithium salts currently represent the recommended first line choice for treatment and prevention of bipolar disorder in all international guidelines, including WHO.
  • lithium is still the most effective drug for prevention of suicidal behaviour, the leading cause of death in BD patients.
  • lithium is administered also to patients presenting with a risk of suicidal behaviour although they do not benefit from the stabilizing effect.
  • lithium represents to date the therapy of choice in bipolar disorder, the relatively high number of non-responsive or partially responsive patients and the possibility of even serious adverse events demand for identification of effective tools for assessment of lithium response in BD subjects. Summary of the invention
  • the inventors have performed a phenotypic characterization of the lithium response by using the retrospective criteria of long-term treatment response scale.
  • Affymetrix 6.0 single nucleotide polymorphism (SNP) array approximately 900,000 SNPs were genotyped in a sample of 52 bipolar patients, selected within a sample of 204 patients, and evenly distributed to the extreme ends of the treatment response scale. Among SNPs that were found to be associated, 1 1 were selected for validation, and genotyping was extended to the rest of the sample. This association was also tested using the scale as quantitative trait. In the subgroup of 52 subjects with bipolar disorder, 50 SNPs were nominally associated with lithium response (p ⁇ 10 "5 ). Some association signals were subsequently confirmed in the extended sample.
  • Results indicate that the ACCN1 gene is a candidate for response to lithium treatment, thus can be used as genetic marker for prediction of lithium efficacy in the treatment of patients with bipolar disorder.
  • object of the invention is a method for diagnosis, in a patient affected by bipolar disorder, of the potential response to treatment with lithium salts, wherein said method comprises the step of determining in a sample the genotype of the patient at the gene locus corresponding to SNP rs1 1869731 of the amiloride-sensitive cation channel 1 , neuronal (ACCN1 ) gene.
  • FIG. 1 Structure of the ACCN1 gene.
  • Figure 2 Box plot of quantitative analysis of the total score of retrospective evaluation scale for lithium response in a sample of 204 bipolar Sardinian patients: stratification according to rs1 1869731 SNP genotypes of the ACCN1 gene.
  • This scale consists of two Criteria: Criterion A: quantifying the degree of improvement during treatment, and Criterion B: determining, by the evaluation of 5 variables, whether the observed improvement results from the stabilizing treatment or spontaneous improvement or effects of additional therapies.
  • Criterion A quantifying the degree of improvement during treatment
  • Criterion B determining, by the evaluation of 5 variables, whether the observed improvement results from the stabilizing treatment or spontaneous improvement or effects of additional therapies.
  • TS Total Score
  • GWS detected 50 SNPs with a significant nominal association with lithium response (with p-values from 10 "5 to 10 "6 ).
  • 1 1 SNPs were then selected and genotyped in the same sample composed of 52 bipolar subjects. Selection of SNPs was made according to the following inclusion criteria: a) association p value ⁇ 10 "5 ; b) SNP position in the gene (priority for intron/exon SNPs), c) possible relevance of the gene in mood disorders and/or in the mechanism of lithium action.
  • Validated SNPs were subsequently genotyped in the rest of the sample and the two datasets were combined (a total of 204 subjects).
  • the ACCN1 gene (RefSeq NC_000017.10 NT_010799.15) is located in the chromosome region 17q12 at position 31 ,340,105-32,483,551 (Ensemble database).
  • the rs1 1869731 polymorphism is located at position 32,338,871 (Ensemble database):
  • the frequency of C allele in the Caucasian population is 78%, while it is 22% for the G allele (HapMap database).
  • object of the invention is a method for diagnosis, in a patient affected by bipolar disorder, of the potential response to treatment with lithium salts, wherein said method comprises the step of determining in a sample the genotype of the patient at the gene locus corresponding to SNP rs1 1869731 of the amiloride- sensitive cation channel 1 , neuronal (ACCN1 ) gene.
  • G/G genotype was found to be associated with mean TS values of 7.35 (full response) while G/C and C/C genotypes were found to be associated, respectively, with 3 and 4 points lower mean TS values compared to the G / G genotype.
  • Polymorphism was genotyped in the sample of bipolar patients using Affymetrix Microarray Genome Wide SNP 6.0 (prob set ID SNP_A-8483155) and was subsequently validated by PCR using the KASParTM technique (http://www.kbioscience.co.uk reaqents/KASP/KASP.html).
  • the invention relates to a method for diagnosis of the potential response to treatment with lithium salts in a patient affected by bipolar disorder, wherein said method comprises the step of determining, in a sample, the patient's genotype at the gene locus corresponding to SNP rs1 1869731 of the amiloride-sensitive cation channel 1 , neuronal (ACCN1 ) gene wherein when the genotype is G/G, the potential response to treatment with lithium salts is favourable or corresponds to a "full response".
  • the patient can be defined as "responder”.
  • the invention relates to a method wherein, when the genotype is G/C, the potential response to treatment with lithium salts is partially positive and the patient may be defined as "partial responder", and when the genotype is C/C, the potential response to treatment with lithium salts is unfavourable and the patient can be defined as "non-responder".
  • the invention relates to a method wherein said sample comprises a nucleic acid and wherein said nucleic acid comprises intron 1 of the ACCN1 gene.
  • the method according to the present invention includes a step for determining in a sample the genotype of the patient, thereby involving the use of at least one oligonucleotide.
  • the ACCN1 gene encodes the acid sensitive ion channel 2 (ASIC 2), a member of the degenerin/epithelial sodium channel (Deg/EnaC) superfamily. This cation channel is primarily permeable to Na + and to a lesser extent to Li + and K + , and is widely expressed in neurons.
  • the ASIC family comprises at least three subunits (ASIC1 , ASIC2 and ASIC3) which assemble into complexes to form channels activated by extracellular protons, with different sensitivity to pH [13, 14].
  • ASICs are apparently key elements in pathophysiology of pain, ischemic stroke and psychiatric diseases [15].
  • transgenic mice over- expressing the ASIC1 subunit exhibit alterations of hippocampal-dependent LTP and of spatial memory, as shown by Morris maze tests [15, 16].
  • treatment of cortical neurons with an acid solution has been reported to induce substantial cellular damage which is attenuated by blockage of ASICI a [17].
  • ASIC1 ASIC1
  • ASIC2 ASIC2 interacts with both ASIC1 and ASIC3 [14]. More specifically, ASIC2 has been reported to modulate H + currents activated by ASIC1 in hippocampal neurons in mice [18].
  • the sample consisted of 204 bipolar patients not related to each other, enrolled at the Lithium Clinic of the Centre for Clinical Pharmacology, Clinical Pharmacology Unit, University Hospital of Cagliari and Department of Neurosciences "BB Brodie", University of Cagliari, Italy. The Dnrolment period was from 1980 to 2006. The mean duration of lithium treatment of patients was 1 1 .49 ⁇ 7.93 years.
  • the diagnosis was made by clinical psychopharmacologists according to Research Diagnostic Criteria (RDC) [22] by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) [23] and a systematic review of patient records.
  • RDC Research Diagnostic Criteria
  • SADS-L Schedule for Affective Disorders
  • SADS-L Schedule for Affective Disorders and Schizophrenia-Lifetime Version
  • the clinical course of each patient was graphically represented by the NIMH Life Chart method.
  • the scale for assessment of the lithium response was then applied to the data thus collected in order to determine the efficacy of the prophylactic treatment [8].
  • the scale quantifies the degree of improvement during treatment (A Score) expressed as a measure of the variation of frequency and severity of disease episodes.
  • the A Score is weighed for 5 factors (B Score) thus making possible to assess whether observed improvements are due to the stabilizing treatment rather than spontaneous improvement or the effect of other drugs.
  • the Total Score (TS), consisting of 1 1 points, is obtained by subtracting the B Score from the A Score.
  • TS Patients with TS equal to or greater than 7 are identified as “full responders” (FR) and patients with TS lower than 7 are identified as “partial” and “non-responders” (and grouped with the designation "other”).
  • 3 different analytical approaches were applied in order to quantify genotype-phenotype correlation: i) selection of patients at the two extreme ends of the lithium treatment response scale in order to emphasize phenotypic differences and possible genetic differences between the two groups, ii) dichotomization of the "response" phenotype by application of a cut-off of TS>7 in order to include a larger sample composed of patients representing the whole response variability to therapy, iii) evaluation of differences among mean TS, using an approach for quantitative traits.
  • Genotyping was performed using Affymetrix GeneChip SNP 6.0 arrays, using the protocol provided by the manufacturer (Affymetrix Inc., Santa Clara, CA, USA) [http://www.affimetrix.com Affymetrix).
  • SNP polymorphisms were created that included markers filtered according to the following criteria: minor allele frequency (MAF)> 0.01 , genotype call rate > 0.97; Hardy Weinberg equilibrium (HWE) p value> 1 x10 "4 . After frequency and genotyping pruning, 261452 of 906600 SNPs were excluded from further analysis. The mean call rate for the remaining 645148 SNPs was > 98%.
  • MAF minor allele frequency
  • HWE Hardy Weinberg equilibrium
  • Fifty SNPs showed nominal association with the lithium response, with a non- corrected p value comprised between 10 "5 and 10 "6 .
  • these polymorphisms are located within or nearby genes encoding G protein-coupled receptors, ion channels, adapter proteins and proteins with zinc finger motifs.
  • Genotyping was performed using the Kbioscience Competitive AlleleSpecific PCR genotyping system (KASP) technique, a fluorescence-based technology that provides reliable results in short time [Kbioscience; http://www.kbioscience.co.uk1. Validation by the KASP method and whole sample genotyping
  • KASP Kbioscience Competitive AlleleSpecific PCR genotyping system
  • the percentage of validation was calculated by comparing the genotypes obtained from microarrays with those obtained by the KASP method.
  • a SNP polymorphism was considered validated if the proportion of discrepancies obtained by the two different methods was ⁇ 0.2%.
  • a genderxgenotype interaction analysis was performed by logistic regression using the Plink software. No significant interaction between study markers and gender (data not shown) was found.
  • genotyping was extended to the remainder of the cohort of bipolar patients that were characterized for their response to lithium (152 bipolar patients), and the two datasets were combined (a total of 204 bipolar patients, see Table 1 ).
  • SNPs As shown in Table 3, four SNPs (rs1 1869731 , rs2499984, rs16909440 and rs16973410) show significant association with the continuous trait, with p-values comprised between 10 "4 and 10 "5 .
  • the most significantly associated SNP polymorphism is rs1 1869731 , with an empirical p value of 4.72 x 10 "5 after 444,555 permutations.
  • Table 3 quantitative trait analysis of retrospective criteria of the long-term treatment response scale in the sample of 204 Sardinian bipolar patients.
  • Kato T Molecular neurobiology of bipolar disorder: a disease of 'mood- stabilizing neurons'? Trends in Neurosci. 31 (10), 495-503 (2008).
  • Firsov D Gautschi I, Merillat AM, Rossier BC, Schild L: The heterotetrameric architecture of the epithelial sodium channel (ENaC).

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Abstract

Le trouble bipolaire est une maladie mentale qui est caractérisée par des épisodes majeurs entrecoupés d'états maniaco-dépressifs, qui affecte de 1 à 5 % de la population, et qui est principalement traitée par des sels de lithium. Tous les patients, toutefois, ne répondent pas à ce traitement. L'invention ci-décrite concerne une méthode d'évaluation pharmacogénétique de la réponse au traitement par des sels de lithium chez les patients atteints de trouble bipolaire, ladite méthode étant basée sur la détection d'un polymorphisme localisé dans l'intron 1 du gène neuronal du canal cation 1 sensible à l'amiloride (ACCN1).
PCT/EP2012/065157 2011-08-03 2012-08-02 Méthode d'évaluation de la réponse pharmacogénétique au traitement par des sels de lithium du trouble bipolaire WO2013017661A1 (fr)

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ITPD2011A000258 2011-08-03
IT000258A ITPD20110258A1 (it) 2011-08-03 2011-08-03 Metodo per la valutazione farmacogenetica della risposta al trattamento con sali di litio nel disturbo bipolare

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Citations (4)

* Cited by examiner, † Cited by third party
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WO2009046395A2 (fr) * 2007-10-04 2009-04-09 The Regents Of The University Of California Procédé pour prédire une réponse à un traitement pour maladies psychiatriques
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Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070122825A1 (en) * 2005-10-07 2007-05-31 The Regents Of The University Of California Method to predict the response to lithium treatment
WO2009046395A2 (fr) * 2007-10-04 2009-04-09 The Regents Of The University Of California Procédé pour prédire une réponse à un traitement pour maladies psychiatriques
WO2009063843A1 (fr) * 2007-11-16 2009-05-22 The University Of Tokyo Procédé de détermination du risque de développer l'obésité sur la base d'un polymorphisme génétique associé à une masse de graisse de corps humain
WO2009101619A2 (fr) * 2008-02-11 2009-08-20 Ramot At Tel-Aviv University Ltd. Procédés pour prédire la réponse d'un patient à un traitement au lithium

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